delta4-11-oxygenated-pregnene-17alpha, 21-diol-3, 20-dione 21-phosphate and salts thereof



Westfield, N. J., assignors to Merck & Co., Inc, Rahway, N; L, a corporation of New Jersey No Drawing. Application August 4, 1954 .Ser'ial No. 447,912

17 Claims. (Cl. 260--397.45)

This inventionrelates to steroids and particularly to phosphate derivatives of .cortisone and hydrocortisone, to

processes for preparing them and to intermediate compoundsthus obtained.

Since thexdiscovery'ofthe remarkable properties of cortisone and hydrocortisone for use in the therapy of arthritis andv related diseases, there has been a widespread interestin finding other steroids and derivatives of these compounds which not only possess the desirable properties of these hormones, but also possess other desirable propertieswhich would make them more adaptable to a wider range of methods of administration. One of -the most desirable properties which'has. been sought for hormones is water solubility. The advantages of having water solubleiform's of cortisone and hydrocortisone are readily apparent. As an example, the facile administration of such hormones dissolved in a water solution allows almost instantaneous utilization of the hormones by the system. When the usual saline suspension of the acetate esters isinjected, however, it requires from 4 to 24 hours before such utilization occurs. This quick action would allow rapid alleviation of diseases requiring hormone therapy.

One of the primary factors which has hindered the search for water-soluble forms or derivatives of cortisone and hydrocortisone is the particular characteristic of these hormones in that many of their derivatives do not maintain the necessary adrenal activity. This may be demonstrated as forexample in the case of cortisone sulfate which exhibits little or no cortical activity.

A primary object of the present invention is to produce water-soluble derivatives of cortisone and hydrocortisone. A related object is to produce such derivatives without any reduction in cortical activity. A further object is to provide processes for producing-these derivatives and intermediates useful in such processes. Other objects and the advantages of the invention will appear hereinafter.

The compounds which are the subject of the invention are phosphate derivatives of steroids having the general formula:

g OH CH2-OP wherein R is an oxygen group thereby forming an ll-keto steroid or a hydrogen and B-hydroxy group thereby forming an ll-p-hydroxy steroid; and salts thereof. These compounds are soluble in a large range of 2 solvents including water, and also maintain the same high cortical activity as cortisone and hydrocortisone.

The compounds of this invention may be prepared by reacting 3-ethylenedioxy-M-pregnene 1711,2l-diol-l 1-R-20- one (Compound I), wherein R is as defined above, with an organic sulfonyl chloride compound to produce the corresponding 3 ethylenedioxy-N -pregnena1'76t,2l-dioll1-R-20-one-2l-sulfonate compound (Compound II). This compound is then treated with an iodide salt to form the corresponding 21-iodo' pregnene"'(Corr'ipound III) which when reacted with an organic phosphate forms the corresponding ZI-organic phosphate 'pregnene compound (Compound IV). Thislatter compound is then hydrogenated in the presence of a hydrogenation catalyst and a tertiary amine to form the corresponding 2l-amine salt of 3-ethylenedioxy-A -pregnene-:,21- diol-1l-R-ZO-one-Zl-phosphate (Compound V). This latter compound ishydrolyzed to produce the 2l-phosphate of cortisone orhydrocortisone (Compound VI) which may be converted to a phosphate salt (Compound Vii) by treating with a basic substance.

As an alternate procedure the 3-ethylenedioxy-A -pregnene 170t,21 -diol l1 R 20 keto 21 sulfonate compound (Compound II) may be prepared by reacting cortisone or hydrocortisone (Compound VIII) with; an organic sulfonylchloride compound to produce the corresponding A preg'nene 170:,21 diol 11 R 3,20- dione-Zl-sulfonatecompound (Compound IX) which is treated with an ethylene dioxy' yielding compound to form the corresponding 3-ethylenedioxy-A -pregnene-17a, 2'1 diol-ll-R-l0 keto-2l-sulfonate compound (Compound II). The A pregnene 17a,21 diol 11 R 3,20- dione-Zl-sulfonate compound (Compound IX) may be reacted with an iodide salt to form 21-iodo-A -pregnenel7 z-ol-11-R-3,20-dione (Compound X) which is then treated with an organic phosphate to produce the corresponding ZI-organic phosphate derivative (Compound XI). This latter compound is reacted with an ethylene dioxy yielding compound to produce the corresponding 3-ethylenedioXy-A -compound (Compound IV).

These reactionsrnay be chemically represented as follows wherein R is as defined above, R is an alkyl group, R is an aryl group, R is a tertiary amine and Y is a metal group and n is a whole integer varying from 1 to 2.

CHnOH O=O on Compound VIII CHr-OS 02R R- i 'R I O i I: v 0

Compound I Compound IX Compound III Compound XI go [Z l Compound V Compound VI The 3-ethylenedioxy-A -pregnene-17a,21-diol-l1-R-20- one, wherein R is as defined above, is reacted with an organic sulfonyl chloride to produce the corresponding 21-sulfonoxy-pregnene compound. The sulfonyl chloride is of the formula R SO CI wherein R is an alkyl group preferably having a carbon chain length of from one to six carbon atoms. Typical examples of such groups are methyl, ethyl and propyl. The reaction is preferably carried out in a solvent such as pyridine or other tertiary amines. The reaction is usually complete in about 1 to 3 hours when the temperature is maintained at approximately 0 C. The product is recovered by diluting the reaction mixture with water and recovering the crystalline material.

The 21-sulfonyl derivative of the 3-ethylenedioxy-A pregnene-l7a,2l-diol-l1-R-20-one is converted to the corresponding 21-iodo compound by treating with an iodide salt. The reaction is conveniently effected by contacting the reactants in a solvent such as an alcohol, ketone or ether. Typical examples of suitable solvents are methanol, ethanol, propanol, methyl butyl ether, ethyl ether, acetone and methyl ethyl ketone. The reaction is preferably carried out at a temperature of approximately 25 to 100 C. and is usually complete in A to 2 hours. The product may be separated from the reaction mixture by the addition of a non-solvent such as water.

The S-ethylenedioxy-Z1-iodo-A -pregnene-17a-ol-1l-R- 20-oue is converted to the corresponding 21-organic phosphate compound by treating with an organic phosphate. The organic phosphate is of the formula where R is an aryl group having a six carbon ring. Examples of such groups are phenyl and substitute phenyls. The organic phosphate is preferably used in the form of a salt such as the silver, sodium, potassium, barium or calcium salt or other metal salts which form insoluble iodides. The reaction is conveniently carried out in the solvent for the reactants such as benzene, toluene, xylene or dioxane and at the reflux temperature of the solvent; The reaction usually requires from 4 to 26 hours for completion. The product may be recovered by the addition of a non-solvent such as an ether.

The 21-organic phosphate compound of 3-ethylencdioxy-A -pregnene-17a,2l-diol-l1-R-20-one is converted to a 21 tertiary amine salt of the 2l-phosphate compound by treating with a tertiary amine (R and hydrogenating in the presence of a hydrogenation catalyst. Suitable tertiary amines are N-methyl morpholine, N-methyl piperidine, dimethylaniline, diethylaniline and trimethylamine. The hydrogenation catalyst may be any of the conventional catalysts such as platinum, nickel or palladium and oxides of these metals. The catalyst may be supported on a suitable carrier such as barium sulfate, calcium carbonate, barium carbonate and the like. The reaction is preferably carried out in a solvent such as an alcohol as for example ethanol, methanol or propanol. The reaction is carried out at approximately 0 to 100 C., preferably at room temperature, until two mols of hydrogen are taken up. The product is separated from the reaction mixture by any of the conventional means such as diluting with water, removing the impurities by extracting with a solvent and concentrating the water solution to dryness.

The 3-ethylenedioxy group of the 21-amine salt is hydrolyzed to form the 21-phosphate of cortisone or hydrocortisone. The hydrolysis may be carried out by treating with a strong acid in a suitable solvent such as acetone, methanol, ethanol, benzene or toluene. Strong acids such as hydrochloric acid, sulfuric acid, perchloric acid and p-toluene sulfonic acid, used in dilute concentrations, are effective for the hydrolysis. The reaction may be carried out from about 20 to 100 C. but is goriveniently effected at the reflux temperature. The rean ethylenedioxy derivative of 2'l-diol-l1-R-3,20-dio-ne may then action is ordinarily complete in from several minutes to 1 hour. A preferred procedure for the hydrolysis is to contact a solvent solution of the 2l-amine salt with an anion exchange resin on the hydrogen cycle. Suitable resins are those shown in U. S. Patents 2,597,494; 2,597,440; 2,570,822; 2,567,836 and 2,543,666. Trade names of specific resins are Amberlite IR-105, Amberlite IRl2O and Amberlite lR-lOO (produced by Rohm & Haas Co.).

The phosphate derivatives of cortisone and hydrocortisone may also be prepared directly from cortisone and hydrocortisone by reacting with an organic sulfonyl chloride compound to produce the corresponding A -pregnene l7a,2l diol ll R 3,20 dione 21 sulfonate compound. The sulfonyl chloride is of the formula wherein R is as defined above. The reaction is preferably "carried out in a solvent such as pyridine, benzene, toluene, tetrahydrofuran or dioxane. The reaction is carried out most effectively at approximately C. and at this temperature the reaction is complete in 1 to 3 hours. The product is recovered by diluting the reaction mixture with Water and recovering the crystalline material.

The n -pregnene-l7a,2l-dioll 1-R-3,20-dioue-21-sulfonate compound may then be converted to the corresponding S-ethylenedioxy derivative. This reaction is conveniently achieved'by reacting with ethylene glycol in the presence of anacid catalyst or by an exchange reaction With an ethylenedioxy yielding compound such as a lower aliphatic ketone such as acetone,'methyl ethyl ketone, mesityl oxide and the like. If desired, this reaction may be effected in an inert solvent such as benzene, toluene, xylene, tetrahydrofuran or dioxane. The reaction proceeds rapidly at an elevated temperature, as for example at the reflux emperature in from 1 to hours. Ordinarily a small amount of a strong acid such as p-toluene sulfonic acid or sulfuric acid is added to enhance the rate of the reaction. Following the completion of the reaction the acid is neutralized With a base, the mixture is diluted with water and the desired product is extracted from the mixture with an immiscible solvent. The product may be isolated by removing the solvent by evaporation under reduced pressure. a

The M-pregnene-l7a,2l-diol-l l-R-3,20-dione-2'1-sulfonate compound may be converted to the corresponding 2l-i-oclo compound by reacting With a suitable iodidesalt. Ordinarily it is preferred to efiect the reaction with an alkali metal salt such as sodium iodide in a solvent such 'as acetone or an alcohol. The reaction proceeds at ordinary temperatures in usually less than one hour. The product may be recovered by adding Water to the mixture, extracting the product and evaporating the solvent.

The 21iodo-A -pregnene-l7aaol-11-R-3,20-dione may be reacted with an organic phosphate :to form the corresponding ZI-organic phosphate compound. The organic phosphate is of the formula (R CH O) PO( OH) wherein R is as defined above. The phosphate is usually used in the form of a salt as for example the silver salt or other metal salts which form insoluble iodides. The reaction is preferably carried out in a solvent such as benzene, toluene, :tetrahy-drofuran or dioxane. The reaction proceeds favorably at the reflux temperature of the solvent. The reaction usually requires from 4 to 20 hours for completion. The product may be precipitated by the addition of a non-polar solvent such as petroleum ether.

The ZI-phosphate derivative of the A -pregnene-17a,

be converted to the corresponding A -3-cthylenedioxy compound. This reaction is conveniently achieved by reaction with ethylene glycol in the presence of an acid catalyst or by an exchange reaction with an iethylenedioxy yielding compound such as an ethylenedioxy derivative of a lower aliphatic ketone such as acetone, methyl ethyl ketone, mesityl oxide and the like. If desired, this reaction may "be effected inaninert solvent such as benzene, toluene, ttetrahydnofuran ctr dioxane. The reaction proceeds rapidly at elevated temperatures-as for example, at the reflux temperature the reaction is complete in 1 to 5 hours. Ordinarily a small amount of strong acid such as p-toluene sulfonic acid or sulfuric acid is added to enhance the rate of reaction. Following completion of the reaction the acid is neutralized with a base, the mixture is diluted with Water and the desired product is extracted from the mixture with an immiscible solvent. The product may be isolated by removing the solvent by evaporation under reduced pressure.

The salts of the Z-i-phosphate derivative of cortisone and hydrocontisone may be prepared byreacting the compound with an aqueous solution of alkali or alkaline earth bases or salts such as hydroxides, carbonates, bicarb onates or acetates. The product may be recovered by :the addition of a HOl'l-S'OlVfilJfitO precipitate the salt. Typical examples of salts which may be'i ormed are sodium, calcium, potassium, magnesium, barium, ammonium and the like. By controlling the amount of reactants both the mono and the di salts may be fiormed.

Table 1 demonstrates the activity of Ithe 21-phosph'ates. The data is the result of one day liver glycogen tests in mice by oral administration.

8 mice receiving 5 hourly doses of the phosphate or free alcohol, subcutaneously or orally. The total dose was 40 of cortisone alcohol per 10 gm. weight of the mouse, or its molecular equilvalent of the phosphate.

TABLE II Liver Glycogen, Substance Route mg./10 gm.

mouse is c.

Noue 4. 3:|:0. 15 Cortisone A1c0hol. 9. 4:|:0. 56 Oortisoue Phosphate 9. 810. 74 Oortisoue AlcohoL. 11. 7:i:0. 44 Cortisone Phosphate. 10. 5:l:0. 63

The following examples are given for purpose of illustrati-on.

Example 1 3-ETHYLENEDIOXY-A -PREGNENE-1'7a,21-DIOL-11,2O- DION E A 4.72 g. sample of 3-e|thylenedioxy-M-pregnene-17a, Zl-diol-l1,20-dione-21-acetate is suspended in 260 ml. of methanol and the reaction mixture purged four times with nitrogen. Sodium methoxide (0.675 g.) is added and the stirred suspension heated to 60 C. under nitrogen. After five to seven minutes the solution is clear. The heating is continued for on additional five minutes and the reaction mixture cooled to 15 C. Glacial acetic acid (0.84 ml.) and ml. of water are added and the reaction mixture concentrated under vacuum to 250 ml. Anadditional 100 ml. of water is added and the concentration continued to a volume of 200 ml. The slurry is cooled and the solid collected and dried to yield 4.0 g. of product, M. P. 178-18? C. Recrystallization from ethyl acetateapetroleum ether gives 2.6 g., M. P. 198-200" C. Ultraviolet absorption spectra shows E% of 4.4 at 2920 A.

in methanol and an absence of absorption at 2380 A.

Calcd for C H O (4O4.49): C, 68.29; H, 7.97. Found:

Example 2 3-ETHYLENEDIOXY-M-PREGNENE-l7a.21-DIOL-11,20- DION E-21-METHANE-SULFONATE A 1.0 g. sample of 3-ethylenedioxy-M-pregnene-17m, 2l-diol-11,20-dione i-n 8 ml. of pyridine is cooled to C.

and treated with 4 ml. of methanesulfonyl chloride. After standing for -two and one-half hours at 0 C., the reaction mixture poured into 150 m1. of cold water and aged in an ice bath. The crystals are collected and washed Example 3 APREGNENE-17a,21-DIOL 3,11,20-TRIONE-2l- METHANESULFONATE Oortisone (6.0 g.) is dissolved in 40 m1. of pyridine, cooled to 0 C., and treated with 1.6 ml. of methanesulfonyl chloride. After standing for one-half an hour at 0 C., the reaction mixture is poured into 400 ml, of water and the aqueous suspension aged in an ice bath. The crystals are collected, washed with water and dried to give 6.6 g. of product, M. P. 122-124" C. Recrystallization from methanol yields either of two dimorphic forms; M. P. 124-125 C. or M. P. 195196 C. dec. Calcd for C H O S: C, 60.25; H, 6.90; S, 7.31. Found: C, 60.25; H, 7.09; S, 7.61.

Example 4 S-ETHYLENEDIOXY-M-PREGNENE-l7a,21-DI0L11,20-

DIONE-21-METHANESULFOXATE A 1.0 g. sample of A -pregnene-17a,21-diol-3,11,20- trione-Zl-methanesulfonate, 50 mg. of p-toluenesulfonic acid hydrate, ml. of the dioxolane of mesityl oxide and 50 ml. of benzene are refluxed for four hours. The reaction mixture is cooled, washed with sodium bicarbonate solution and then with water. After drying over magnesium sulfate the solution is concentrated to a syrup and taken up in ethyl acetate. The slow addition of petroleum ether precipitates crystals, M. P. 168-175 C. Recrystallization from ethyl acetate yields 150 mg. of substantially pure 3-ethylenedioxy-A -pregnene-170:,21- diol-11,ZO-dione-Zl-methanesulfonate.

Example 5 S-ETHYLENEDIOXY-21-IODO-M-PREGNENE-IIa-OL-ll,20- DIONE A 570 mg. sample of 3-ethylenedioxy-A -pregnene- 17u,21-dio1-11,20-dione-2l-methanesulfonate, 280 mg. of sodium iodide and 35 ml. of ethanol are refluxed for onehalf an hour. The mixture is filtered and the filtrate concentrated to 25 ml. Water (30 ml.) is added and the mixture concentrated to 50 ml. The solid is collected, washed with water and dried to give 510 mg. of product, dec. 123 C. Calcd. for C H IO C, 53.70; H, 6.08. Found: C, 53.81; H, 5.80.

Example 6 3-ETHYLENEDIOXY-A -PREGNENE-l7a,21-DIOL-11,20-

DIONE-Zl-DIBENZYLPHOSPHATE A suspension of 3.63 gm. of 3-ethylenedioxy-2l-iodo- A -pregnene-17a-ol-11,20-dione and 3.2 gm. of silver dibenzylphosphate in 534 ml. of benzene was concentrated at atmospheric pressure to a volume of approximately 321 ml. (213 ml. of benzene distilled). The resultant slurry was refluxed for 20 hours, with protection from moisture. The mixture was filtered while hot and evaporated in vacuo to a volume of 50 ml., and filtered again. By keeping the solution.hot while adding (heptane) Skellysolve b, crystals of 3-ethylenedioxy-A -pregnene- Cal S 17a,21- 1i0l-l1,20 dione 21 dibenzylphosphate formed. If the mixture was allowed to cool before complete crystallization had occurred the gelatinous form of the product would appear in the supernatant. Reheating and keeping hot during the crystallization period aiforded all crystalline material. The crystals were collected, washed with ethyl ether and air dried. The product, 3-ethylenedioxy-A -pregnene-170;,21- diol-l 1,20- dione 21 -dibenzylphosphate, was redissolved and treated with Darco G-60, reprecipitation of the product as above resulted in 1.98 gm. of crystalline material, M. P. 151.5 C. Calcd. for C H O P: C, 66.85; H, 6.82; P, 4.66. Found:

C, 67.00; H, 6.64; P, 4.56.

Example 7 2l-IODO-A -PREGNENE-17a-OL-3,11,20-TRIONE A 500 mg. sample of A -pregnene-17a,21diol-3,20-

dione-2l-methanesulfonate in 30 ml. of acetone is treated with 220 mg. of sodium iodide. After refluxing for 10 minutes, the mixture is filtered and the filtrate concentrated to 20 ml. Water (50 ml. is added, the mixture cooled and the crystals collected and washed with water and dried to give 420 mg. of product; dec. -175 C. Recrystallization from acetone-petroleum ether gives crystals, dec. -175 C. Calcd: I, 26.98. Found: I, 26.72.

Example 8 ALPREGNENE-IM 21-DIOL-3,11.20-TRIONE-21- DIBENZYLPHOSPHATE A 1.6 g. sample of 21-iodo-A -pregnene-17a-ol-3,11, ZO-tn'one and 1.45 g. of silver dibenzylphosphate are suspended in 150 ml. of benzene and 25 ml. of solvent distilled therefrom to dry the system. The mixture is refluxed for sixteen hours and filtered while hot. The residue is washed with warm benzene and the combined filtrates concentrated to a syrup which crystallized. The syrup is crystallized from benzene-petroleum ether mixture to give 1.9 g. of product, M. P. 147-l49 C. A portion recrystallized from acetone-petroleum ether, M. P. 160-l62 C. Calcd. for C H O P: P, 4.99. Found: P, 4.68.

Example 9 3-ETHYLENEDIOXY-M-PREGNENE-l70.21-DIOL-11,20- DIONE-ZI-DIBENZYLPHOSPHATE A 1.0 g. sample of M-pregnene-17a,21-diol-3,11,20- trione-Zl-dibenzylphosphate, 0.1 g. of p-toluenesulfonic acid monohydrate, 3.5 ml. of the dioxolane of mesityl A -PREGNENE-17t2.21-DIOL-3,11,20-TRIONE-21- PHOSPHATE 1.0 g. of 3-ethylenedioxy-A -pregnene-17a,2l-diol-l1, 20-dione-2l-dibenzylphosphate is dissolved in 100 ml. of ethanol containing 4 ml. of N-methylmorpholine and hydrogenated at room temperature and atmospheric pressure in the presence of 1.0 g. of palladium oxide which has been pro-reduced. The reaction mixture is filtered and concentrated in vacuo to a syrup. The syrup is dissolved in Water and extracted with ethyl acetate and then ether. The aqueous layer is concentrated to dryness to give 820 mg. of solid N-methylmorpholine salt of 3-ethylenedioxy -A pregnene -17oz,2l diol 11,20 dione -2 l-phosmethanol is shaken over night with 640 mg. of phate. A 360 mg. sample of this solid in 20 ml. of methanol dried Amberlite IR-120 (ion exchange resin) Example 11 SODIUM SALT OF N-PREGNENE-17a,21-DIOL-3,11,20-

. TRIONE-2l-PHOSPHATE The cortisone phosphate treated with 45 mg. of sodium bicarbonate in 2 ml. of water. The whole is concentrated to dryness and the residue taken up in Water and shaken out with ethyl acetate. The aqueous layer is concentrated to dryness, dissolved in methanol and 1:1 absolute ether-ethanol added to precipitate sodium cortisone phosphate. A max. 238, E% 290, [a] |145 (C=1, methanol).

Example 12 A PREGNENEJIB,17u,21-TRIOL-3,20-DIONE-21- PHOSPHATE The compound A -pregnene-11B,17a,21-triol-3,20-dione-2l-phosphate is prepared by the procedure of Examples 1 to by using 3-ethylenedioxy-A -pregnene- 11,8,17a,21-triol-20-0ne and M-pregnene-l113,17a,21-triol- 3,20-dione respectively as the starting material in Examples 1 and 3.

Example 13 POTASSIUM SALT OF A -PREGNENE-17a,21-DIOL-3,11,20-

TRIONE-Zl-PHOSPHATE A methanol solution of A -pregnene-17a,21-dio1- 3,11,20-trione-21-phosphate is treated with two equivalents of potassium bicarbonate in the same manner as described for the sodium salt in Example 11. The monosalt is prepared by treating with one equivalent of potassium bicarbonate.

Example 14 AMMONIUM SALT OF A -PREGNENE17a,21-DIOL-3,11,20- TRIONE-21-PHOSPHATE A solution of A -pregnene-17a,21-diol-3,11,20-trione- Ill-phosphate is treated with twoequivalents of dilute ammonium hydroxide solution to form the diammonium salt. The mono-salt is prepared by treating with one equivalent of ammonium hydroxide. The product was separated as in Example 11. 7

Example 15 SODIUM SALT OF N-PREGNENE-l1B,17a,21-'IRIOL-3,20- DIONE-21-PHOSPHATE A solution of A -pregnene-11 3,17a,21-triol-3,20-dionc- 21-phosp'hate is treated with two equivalents of sodium bicarbonate. The mono-sodium salt is prepared by treating with one equivalent of bicarbonate. The product is separated as in Example 11.

Example 16 POTASSIUM SALT OF M-PREGNENE-l1B,17a,21-TRIOL- 3,20-DIONE-21-PHOSPHATE A solution of A -pregnene-1118,l7a,2l-triol-3,20-dione- 2l-phosphate is treated with two equivalents of potassium bicarbonate to form the dipotassium salt. The mono-potassium salt is prepared by treating with one equivalent of potassium bicarbonate. The product is separated as in Example 11.

Example 17 3-ETHYLENEDlOXY-A -PREGNENE-17a,21-DIOL-11,20- DION E V tonitrile-ether yields 21 1G and the mixture was rapidly cooled to 10-15" C. The solution is acidified with'0.85 ml. of glacial acetic acid 13.5 millimols), diluted with IIlluOf water, and concentrated in vacuo 'to 200 ml. Anadditional 100 ml. of water is added, and the concentration is continued to a final volume of ml. The resulting slurry'is cooled in ice, and the solid is collected, washed with,water and dried in air. Recrystallization from ethyl acetateyields substantially pure 3-ethylenedioxy-fi-pregnene-l 762,21

diol-1l,20-'dione, M.-P. 198-200 C.

' Example 18 A solution of 2 1.5 (0.06 mol) or '3.-ethylenedioxy- ,M-pregnene-l7a,2'l-diol-l1,20-dione in 200 m1. of dry pyridine is cooled to 0 Grand treatedwith 7.5 ml. (0.1 mol) of methanesulfonyl chloride. LAfterstanding 2 /2 hours at 0 C., the reaction mixture-is pouredl int o 8.5 liters of cold water and aged for a half-hour in an ice bath. The crystals are collected andwashed with water, methanol, andfinally ether. Recrystallization fromaceg. of 3-ethylenediOXyQA -pregnene- 17a,21-dio1-11,20-dione 21-methanes'ulfonate, M. P. 201-- Example 19 3-ETHYLENEDIOXY-Z1-IODO-A -PREGNENE-17a-OL-11,20- DION E Example 20 3-ETHYLENEDIOXY-M-PREGNENE 1'7a,21-DIOL-11,20- DIONE 21-DIBENZYLPHOSPHATE A suspension of 13.5 g. 3-ethylenedioxy-21-iodo-A pregnene-17a-ol-11,20-dio-ne and 12 g. of silver dibenzyl phosphate [prepared as described in Sheehan, J. Am. Chem. Soc., 72, 1312 (1950)] in 2 liters of benzene is evaporated (atmospheric pressure) to 1.2 liters volume, and then boiled under reflux for 20 hours, with protection from moisture. The mixture is filtered while hot, evaporated to 200 ml., filtered again, and then diluted with petroleum ether to a slight turbidity. The mixture is cooled to 0 C., and the crystals of 3-ethylenedioxyn -pregnene-17a,21-diol-11,20 dione 21 dibenzylphosphate which precipitated are collected, washed well with ether, and air dried. Yield 13.4 g., M.' P. 7075 C.

Example 21 3-ETHYLENEDIOXY-A -PREGNENE-l7d.21-DI0L-11,20- DIONE 21-PHOSPHATE, N-METHYLMORPHOLINE SALT A suspension of 5.0 g. of palladium oxide (PdO) in 500 ml. of absolute ethanol and 10 m1. of N-methylmorpho-line is reduced at 40 p. s. i. until no more hydrogen was taken up. Then 5.0 g. of solid 3-ethylenedioxy-A pregnene-17a,21-diol-l1,20-dione 2l-dibenzylphosphate is added and the reduction is continued until two additional equivalents of hydrogen are absorbed. The reduction is stopped, the catalyst is filtered off, and the resulting solution is evaporated in vacuo to about 40 ml. The mixture, containing some crystalline material, is cooled to- 0 C., and the crystalline 3-ethylenedioxy-A -pregnene- 17a,21-diol-11,20-dione ZI-phosphate, N-methylmorpholine salt is collected, washed with ethanol, then with ether, and air dried. Yield, 3.3 g., M. 9. 195410 c.

1 1- Example 22 SODIUM SALT OF CORTISONE 21-PHOSPHATE Ten grams of 3-ethylenedioxy-A -pregnene-l7e,21- diol-11,20-dione 2l-phosphate, N-methylmorpholine salt are dissolved in 500 ml. of methanol and 20 g. of Amberlite IRC-120 (hydrogen cycle) is added. The mixture is shaken over night (16-20 hours) and then the resin is removed. The solution containing cortisone phosphate is treated with 2.5 g. of sodium bicarbonate .(2 equivalents) in 5 ml. water and then evaporated to 5 ml. at 25 C. The residue is taken up in 100 ml. of water; this aqueous solution is extracted with ethyl ace tatev and ether, and then lyophilized. The resultant solid is taken up in 100 ml. of methanol, the solution is filtered, and the amorphous sodium salt of cortisone phosphate, is precipitated with 200 ml. of ether. This material is collected, washed with ether and petroleum ether, and then dried in air. Yield 6.0 g., max. 238, E% 290, [a] +l4-5 (C=1, methanol).

Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.

What is claimed is:

1. A compound selected from the group consisting of compounds having the structural formula on T CHr-OP wherein Z is a radical selected from the group which consists of keto and hydroxy radicals, and alkali metal, alkaline earth metal, ammonium and amine salts thereof.

2. A pregnene 113370 21 triol 3,20 dione 21- phosphate having the structural formula 3. A preguene 1711,21 diol 3,11,20 trione 21- phosphate having the structural formula 4. Sodium salt of A pregnene-11B,17a,21-triol-3,20- dione-Zl-phosphate having the structural formula g OH CHr-OP 5. Sodium salt of A -pregnene-l7a,21-dio1-3,11,20- trione-21-phosphate having the structural formula g OH CHr-OP 6. Potassium salt of A -pregnene-17a,21-diol-3,l1,20- trione-Zl-phosphate having the structural formula (12 OH GET-0P 7. The process which comprises reacting 3-ethylenedioxy-A -pregnene-l7a,2l-diol-ll-R-20-one wherein R is selected from the group consisting of keto and fl-hydroxy with an organic sulfonyl compound to produce the corresponding 21-sultonoxy-pregnene compound, reacting the latter compound with an iodide salt to form 3-ethylenedioxy 21 iodo A pregnene 17a ol 11 R 20- one, reacting this compound with an Organic phosphate to form the corresponding 2l-organic phosphate compound, hydrogenating the 21-organic phosphate compound in the presence of a hydrogenation catalyst and a tertiary amine to form a tertiary amine salt of 3-ethylenedioxy- A -pregnene-l7a,2l-diol-l1-R-20-one-2l phosphate and hydrolyzing the amine salt to form A -pregnene-17a,2ldiol-l 1-R-3,20-dione-2 l-phosphate.

8. The process which comprises reacting 3-ethyleuedioxy-A -pregnene-17a,2l-diol-l1,20-dione with an organic sulfonyl compound to produce the corresponding 2l-sulfonoxy-pregnene compound, reacting the latter compound With an iodide salt to form 3-ethylenedioxy-2liodo-M-pregnene-17a-o1-11,20-dione, reacting this compound with an organic phosphate to form the corresponding Zl-Organic phosphate compound, hydrogenating the 2l-organic phosphate compound in the presence of a hydrogenation catalyst and a tertiary amine to form a tertiary amine salt of 3-ethylenedioxy-A' -preguene-17a, 21-diol-11,20-dione-21-phosphate and hydrolyzing the amine salt to form A -pregnene-l7a,2l-diol-3,11,20-trione-21-phosphate.

9. The process which comprises reacting S-ethylenedioxy-A' -pregnene-11}8,17a,21-triol-20-one with an organic sulfonyl compound to produce the corresponding 21-sulfonoxy-pregnene Compound, reacting the latter compound with an iodide salt to form 3-ethyleuedioxy-21- 13 iodo-A -pregnene-l7a-ol-l1,20-di0ne, reacting this compound with an organic phosphate to form the correspond ing 2l-organic phosphate compound, hydrogenating the 2l-organic phosphate compound in the presence of a hydrogenating catalyst and a tertiary amine to form a tertiary amine salt of 3-ethylenedioxy-A -pregnene-11p, l7u,2l-triol-20-one-2lphosphate and hydrolyzing the arnine salt to form M-pregnene-l1fi,17a,21-triol-3,2G- dione-Zl-phosphate.

10. The process which comprises reacting 3-ethylencdioXy-A -pregnene-17a,2l-diol-l1,20-dione with methane sulfonyl chloride to form 3-ethylenedioxy-M-pregnene- 17a,21-di01-1 1,20-dione-2l-methanesulfonate, reacting this latter compound with sodium iodide to form 3-ethylencdioxy 21 iodo A -pregnene 17cc o1 11,20 (lion-1 reacting this compound with silver dibenzyl phosphate to form 3 ethylenedioxy A pregnene 17a,2l diol- 1l,ZO-dione-Zl-dibenzylphosphate, hydrogenating the 2.1- dibenzyl-phosphate compound in the presence of palladium oxide and N-methylmorpholine to form a 12 methylmorpholine salt of 3-ethylene-dioXy-A pregneno 170:,21-di0l-11,20-dione-21-phosphate and treating the amine salt with an ion exchange resin to form A -pregnene-l 7a,2 l -diol-3 ,l1,20-trione-21-phosphate.

11. The process which comprises reacting S-ethylenedioxy-A' -pregnene-1lfi,17a,21-triol-20-one with methanesulfonyl chloride to form 3-ethylenedioXy-A pregnenel1,8,17u,21-triol-20-one-2l-methanesulfonate, reacting this latter compound with sodium iodide to form B-ethylenedioxy-Z l-iodo-A -pregnene-1 1B,l7a-diol-20-one, reacting this compound with silver dibenzylphosphate to form 3- ethylenedioxy A pregnene 11,8,17a,21 triol 20- one-2l-dibenzylphosphate, hydrogenating the Zl-dibenzylphosphate compound in the presence of palladium oXide and N-methylmorpholine to form a N-methylmorpholine salt of 3-ethylenedioxy-n -pregnene-11,8, 70,21-i1i0i-20- 0ne-21-phosphate and treating the amine salt with an ion exchange resin to form M-pregnene-llfi,17x,21-triol- 3,20-dione-2l-phosphate.

12. The process which comprises reacting with a mineral acid hydrolyzing agent a compound having the formula wherein R is a tertiary amine to form A -pregnene-l7u, 21-dio1-3,11,20-trione-21-phosphate.

13. The process which comprises reacting with a mineral acid hydrolyzing agent a compound having the formula 14' wherein R is a tertiary amine to form A -pregnene- 11,8,17,21-triol-3,20-dione-2l-phosphate.

14. The process which comprises reacting A -pregnene- 17tt,2l-diol-3,11,20-trione with an organic sulfonyl com- 1 pound to produce the corresponding 21-organic sulfonate pregnene compound, reacting the latter compound with an ethylenedioxy yielding compound to form the corresponding 3-ethylenedioxy-A -pregnene compound, reacting this compound with an iodide salt to form the corresponding 3-ethylenedioXy-21-iodo-A -pregnene compound, reacting the 21-iodo compound with an organic phosphate to form the corresponding 21-organic phosphate compound, hydrogenating the 21-organic phosphate compound in the presence of a hydrogenation catalyst and a tertiary amine to form a tertiary amine salt of 3-ethylenedioxy- A -pregnene-17 0:,21-di01-1 1,20-dione-2l-phosphate and hydrolyzing the amine salt to form A -pregnene-l7a,21-diol- 3,1 1,20-trione-2 l-phosphate.

15. The process which comprises reacting A -pregnenel1B,l7a,21-triol-3,20-dione with an organic sulfonyl compound to produce the corresponding 21-0rganic sulfonate pregnene compound, reacting the latter compound with an ethylenedioxy yielding compound to form the corresponding 3-ethylenedioxy-M-pregnene compound, reacting this compound With an iodide salt to form the corresponding 3-ethylenedioXy-2l-iodo-A pregnene compound, reacting the 21-iodo compound with an organic phosphate to form the corresponding 21-organic phosphate compound, hydrogenating the 21-organic phosphate compound in the presence of a hydrogenation catalyst and a tertiary amine to form a tertiary amine salt of 3-ethylenedioxy-A pregnenei1,8,17rx,21-triol-20-one-2l-phosphate and hydrolyzing the amine salt to form M-pregnene-l15,17a,21-triol-20-one- 21-phosphate.

16. The process which comprises reacting A -pregnene 17a,2l-diol-3,l1,20-trione with an organic sulfonyl compound to produce the corresponding 2l-organic sulfonate pregnene compound, reacting the latter compound with an ethylenedioxy yielding compound to form the corresponding 3-ethylenedioxy-M-pregnene compound, reacting this compound with an iodide salt to form the corresponding 2l-iodo compound, reacting this compound with an organic phosphate to form the corresponding 2l-organic phosphate compound, hydrogenating the 2l-organic phosphate compound in the presence of a hydrogenation catalyst and a tertiary amine to form a tertiary amine salt of 3-ethylenedioxy-A -pregnene- 17a,21-diol-11,20-dione-2l-phosphate and hydrolyzing the amine salt to form A -pregnene-17a,21-diol-3,11,20-trione- 2l-phosphate.

17. The process which comprises reacting A -pregnene- 11,3,170c,2l-tl'lO1-3,20-di0l'l6 with an organic sulfonyl compound to produce the corresponding 2l-organic sulfonate pregnene compound, reacting the latter compound with an iodide salt to form the corresponding 21-iodo compound, reacting this compound with an organic phosphate to form the corresponding 21-organic phosphate compound, reacting the 21-organic phosphate compound with an ethylenedioxy yielding compound to form thecorresponding 3ethylenedioxy-A -pregnene compound, hydrogenating the 3-ethylenedioxyM-pregnene compound in the presence of a hydrogenation catalyst and a tertiary amine to form a tertiary amine salt of 3-ethylenedioxy-A pregnene-11,3,17a,21-triol-20-one-2l-phosphate and hydrolyzing the amine salt to form M-pregnene-I 119,111,21- triol-3,20-dione-21-phosphate.

References Cited in the file of this patent UNITED STATES PATENTS 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE STRUCTURAL FORMULA 